Measurement of susceptibility to diabetic foot ulcers

ABSTRACT

The present disclosure provides apparatuses and methods for measuring capacitance as an indication of susceptibility to the formation of a diabetic foot ulcer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Nonprovisional Application15/887,886 filed Feb. 2, 2018, which claims the benefit of priority ofU.S. Provisional Application 62/454,482 filed Feb. 3, 2017, and U.S.Provisional Application 62/521,917 filed Jun. 19, 2017, each of which isherein incorporated by reference in its entirety.

FIELD

The present disclosure provides apparatus and methods for assessment ofa foot of a patient at risk for development of diabetic foot ulcers.

DESCRIPTION OF THE RELATED ART

Diabetic foot ulcers are responsible for more hospitalizations than anyother complication of diabetes. Nonenzymatic glycation induced by anelevated level of blood sugar causes ligaments to stiffen and increasescross-linking in collagen. These conditions can lead to damage tocellular walls and blood vessels that result in an initial increase theamount of extracellular fluid (ECF). Peripheral neuropathy causes lossof protective sensation and loss of coordination of muscle groups in thefoot and leg. The neuropathy can cause an increase in the mechanicalstresses within the foot during ambulation and standing that, combinedwith the weakened tissue induced by the diabetes, will progress totissue death if the stress is not reduced. The neuropathy also reducesthe patient’s ability to perceive pain that is normally associated withthe stress and tissue damage, thereby allowing the condition toprogress.

Every year, approximately 5% of diabetics develop a foot ulcer and 1%will require amputation of a digit or some portion of the foot. Longterm, 15% of patients with diabetes will develop a foot ulcer and 12-24%will require amputation. Diabetes is the leading cause of nontraumaticlower extremity amputations in the United States. 20-30% of the overallcost of treating diabetes is related to the treatment and healing offoot ulcers after they occur.

The current approach to the prevention of diabetic foot ulcers ispatient education, foot skin and toenail care, appropriate footwearselection, and proactive surgical intervention. A means of detecting apre-ulcer condition would enable implementation of preventive techniquessuch as offloading and improved hygiene.

SUMMARY

In an aspect, the present disclosure provides for, and includes, anapparatus for assessing susceptibility of tissue to formation of adiabetic foot ulcer, the apparatus comprising: a plurality of electrodesembedded on a substrate, where a pair of the electrodes is capable offorming a capacitive sensor configured to measure a first capacitance ofa first region of tissue proximate to the capacitive sensor, a circuitelectronically coupled to the electrodes, a processor electronicallycoupled to the circuit, and a non-transitory computer-readable mediumelectronically coupled to the processor and comprising instructionsstored thereon that, when executed on the processor, perform the stepsof: receiving information from the circuit regarding the measured firstcapacitance from the capacitive sensor, comparing the measured firstcapacitance to a first reference value, and providing a signal if themeasured first capacitance differs from the first reference value by anamount greater than a first predetermined threshold.

In one aspect, the present disclosure provides for, and includes, amethod for assessing susceptibility of tissue to formation of a diabeticfoot ulcer, the method comprising: obtaining a first capacitance valueat a first location of a patient’s skin; obtaining a temperaturemeasurement at the first location of a patient’s skin; and determiningthat the first location of a patient’s skin is susceptible to formationof a diabetic foot ulcer when the first capacitance value differs fromthe first reference value by an amount greater than a firstpredetermined threshold and the temperature measurement differs from thesecond reference value by an amount greater than a second predeterminedthreshold.

In an aspect, the present disclosure provides for, and includes, amethod for assessing susceptibility of tissue to formation of a diabeticfoot ulcer, the method comprising: obtaining a first sub-epidermalmoisture (SEM) value at a first location of a patient’s skin; obtaininga temperature measurement at the first location of a patient’s skin; anddetermining that the first location of a patient’s skin is susceptibleto formation of a diabetic foot ulcer when the first SEM value differsfrom the first reference value by an amount greater than a firstpredetermined threshold and the temperature measurement differs from thesecond reference value by an amount greater than a second predeterminedthreshold.

In one aspect, the present disclosure provides for, and includes, anintegrated apparatus for treating a diabetic foot ulcer in a patient inneed thereof, said apparatus comprising: a plurality of sensors disposedon a flexible substrate, wherein the plurality of sensors are configuredto measure sub-epidermal moisture (SEM) values at respective locationsof the patient’s skin; two electrodes disposed on the flexiblesubstrate; and an external controller electrically connected to the twoelectrodes, where the external controller controls the two electrodes todetect conductive contact with the patient’s skin during a SEMmeasurement period, and the external controller controls the twoelectrodes to apply a therapeutic stimulus to the patient during atherapeutic phase.

In an aspect, the present disclosure provides for, and includes, anintegrated apparatus for treating a diabetic foot ulcer in a patient inneed thereof, the apparatus comprising: a sensor comprising twoelectrodes disposed on a flexible substrate such that a current passingbetween the electrodes will pass through tissue proximate to a locationof the patient’s skin; and an external controller electrically connectedto the two electrodes.

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the disclosure are herein described, by way of example only,with reference to the accompanying drawings. With specific reference nowto the drawings in detail, it is stressed that the particulars shown areby way of example and are for purposes of illustrative discussion ofaspects of the disclosure. In this regard, the description and thedrawings, considered alone and together, make apparent to those skilledin the art how aspects of the disclosure may be practiced.

FIG. 1A depicts the anatomy of a foot.

FIG. 1B is an enlarged view of area A of FIG. 1A.

FIG. 2A depicts an initial open ulcer at time_0.

FIG. 2B depicts the pressure profile created in the condition of FIG.2A.

FIG. 2C depicts the same region of tissue of FIG. 2A at time_1.

FIG. 2D depicts the same region of tissue of FIGS. 2A and 2C at time_2.

FIG. 3A discloses a toroidal bioimpedance sensor.

FIG. 3B discloses an idealized field map created by the toroidal sensorof FIG. 3A when activated.

FIG. 3C discloses a SEM scanner that comprises the sensor of FIG. 3A.

FIG. 4 is a first exemplary array of electrodes.

FIG. 5 is an exemplary array of electrodes according to the presentdisclosure.

FIG. 6A illustrates a first example of how the array of electrodesdisclosed in FIG. 5 is configured to form a bioimpedance sensoraccording to the present disclosure.

FIG. 6B illustrates a first example of how the array of electrodesdisclosed in FIG. 5 is configured to form a bioimpedance sensoraccording to the present disclosure.

FIG. 6C illustrates an example of a first sensor formed in an array ofelectrodes according to the present disclosure.

FIG. 6D illustrates an example of how a second sensor is formed tooverlap with the first sensor of FIG. 6C according to the presentdisclosure.

FIG. 6E shows an example of how sensors as shown in FIG. 6A are formedfrom an array of electrodes that is larger than the portion of thepatient’s skin that is being positioned against the array, according tothe present disclosure.

FIG. 6F illustrates locations on the left and right feet for SEMmeasurements according to the present disclosure.

FIG. 6G is a plot of SEM values associated with known relative locationsfor identifying bisymmetric locations according to the presentdisclosure.

FIG. 7A depicts a first example of a mat assembly that incorporates aplurality of bioimpedance sensors according to the present disclosure.

FIG. 7B depicts a second example of a mat assembly that comprises arraysof electrical sensors, according to the present disclosure, disposed soas to underlie the left and right feet, respectively, of a patient whilestanding on the mat assembly.

FIG. 7C depicts a third example of a mat assembly that comprises one ormore sensors disposed within each of the outlines according to thepresent disclosure.

FIG. 8A discloses a foot cover that incorporates bioimpedance sensorsaccording to the present disclosure.

FIG. 8B is a cutaway view of the foot cover of FIG. 8A, showing thelocation of the bioimpedance sensors according to the presentdisclosure.

FIG. 9 disclose a sandal that incorporates bioimpedance sensorsaccording to the present disclosure.

FIG. 10A depicts a first example configuration of the addressableelectrodes of FIG. 5 that vary the performance capabilities of thesensor according to the present disclosure.

FIG. 10B depicts a second example configuration of the addressableelectrodes of FIG. 5 that vary the performance capabilities of thesensor according to the present disclosure.

FIG. 10C depicts a third example configuration of the addressableelectrodes of FIG. 5 that vary the performance capabilities of thesensor according to the present disclosure.

FIG. 11A shows an exemplary configuration of a substrate shaped to bepositioned in a known position on a patient’s skin according to thepresent disclosure.

FIG. 11B shows a front view of the exemplary configuration of FIG. 11Aaccording to the present disclosure.

FIG. 12 depicts a schematic depiction of an integrated system formeasurement, evaluation, storage, and transfer of SEM values accordingto the present disclosure.

FIG. 13 depicts a sensing band according to the present disclosure.

FIGS. 14A, 14B, and 14C depict an integrated sensor and stimulatorassembly suitable for treatment of a pressure ulcer, according to thepresent disclosure.

FIG. 14D depicts a bandage assembly suitable for treatment of a pressureulcer, according to the present disclosure.

FIG. 15A illustrates an exemplary method for taking SEM measurementsstarting at the posterior heel in accordance with the presentdisclosure.

FIG. 15B illustrates an exemplary method for taking SEM measurementsstarting at the lateral heel in accordance with the present disclosure.

FIG. 15C illustrates an exemplary method for taking SEM measurementsstarting at the medial heel in accordance with the present disclosure.

DETAILED DESCRIPTION

The present disclosure describes measurement of various electricalcharacteristics and derivation of SEM values indicative of an increasein the amount of ECF and the application of this information to theassessment of susceptibility to diabetic foot ulcers as well astreatment of ulcers.

Diabetic foot ulcers are known to occur in areas subject to repetitivemoderate loads, particularly in areas where bony portions of the footapply transfer body weight to the adjacent tissue while standing. Damagemay initially occur in tissue below the skin and is, therefore, notdetectable by visual inspection. The initial damage will release fluidinto the extracellular spaces, which can be detected through themeasurement of electrical properties of the sub-epidermal tissue, forexample the capacitance of the tissue. Monitoring the ECF in at-riskareas will detect deterioration of the tissue that, if left unchecked,will progress to an open ulcer.

This description is not intended to be a detailed catalog of all thedifferent ways in which the disclosure may be implemented, or all thefeatures that may be added to the instant disclosure. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. Thus, thedisclosure contemplates that in some embodiments of the disclosure, anyfeature or combination of features set forth herein can be excluded oromitted. In addition, numerous variations and additions to the variousembodiments suggested herein will be apparent to those skilled in theart in light of the instant disclosure, which do not depart from theinstant disclosure. In other instances, well-known structures,interfaces, and processes have not been shown in detail in order not tounnecessarily obscure the invention. It is intended that no part of thisspecification be construed to effect a disavowal of any part of the fullscope of the invention. Hence, the following descriptions are intendedto illustrate some particular embodiments of the disclosure, and not toexhaustively specify all permutations, combinations and variationsthereof.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. The terminology used in thedescription of the disclosure herein is for the purpose of describingparticular aspects or embodiments only and is not intended to belimiting of the disclosure.

All publications, patent applications, patents and other referencescited herein are incorporated by reference in their entireties for theteachings relevant to the sentence and/or paragraph in which thereference is presented. References to techniques employed herein areintended to refer to the techniques as commonly understood in the art,including variations on those techniques or substitutions of equivalenttechniques that would be apparent to one of skill in the art.

U.S. Pat. Application Serial No. 14/827,375 discloses an apparatus thatuses radio frequency (RF) energy to measure the sub-epidermalcapacitance using a bipolar sensor similar to the sensor 90 shown inFIG. 3A, where the sub-epidermal capacitance corresponds to the moisturecontent of the target region of skin of a patient. The ‘375 applicationalso discloses an array of these bipolar sensors of various sizes.

U.S. Pat. Application Serial No. 15/134,110 discloses an apparatus formeasuring sub-epidermal moisture (SEM) similar to the device shown inFIG. 3C, where the device emits and receives an RF signal at a frequencyof 32 kHz through a single coaxial sensor and generates a bioimpedancesignal, then converts this signal to a SEM value.

Both U.S. Pat. Application Serial Nos. 14/827,375 and 15/134,110 areincorporated herein by reference in their entireties.

Unless the context indicates otherwise, it is specifically intended thatthe various features of the disclosure described herein can be used inany combination. Moreover, the present disclosure also contemplates thatin some embodiments of the disclosure, any feature or combination offeatures set forth herein can be excluded or omitted.

The methods disclosed herein include and comprise one or more steps oractions for achieving the described method. The method steps and/oractions may be interchanged with one another without departing from thescope of the present invention. In other words, unless a specific orderof steps or actions is required for proper operation of the embodiment,the order and/or use of specific steps and/or actions may be modifiedwithout departing from the scope of the present invention.

As used in the description of the disclosure and the appended claims,the singular forms “a,” “an” and “the” are intended to include theplural forms as well, unless the context clearly indicates otherwise.

As used herein, “and/or” refers to and encompasses any and all possiblecombinations of one or more of the associated listed items, as well asthe lack of combinations when interpreted in the alternative (“or”).

The terms “about” and “approximately” as used herein when referring to ameasurable value such as a length, a frequency, or a SEM value and thelike, is meant to encompass variations of ± 20%, ± 10%, ± 5%, ± 1%, ±0.5%, or even ± 0.1% of the specified amount.

As used herein, phrases such as “between X and Y” and “between about Xand Y” should be interpreted to include X and Y. As used herein, phrasessuch as “between about X and Y” mean “between about X and about Y” andphrases such as “from about X to Y” mean “from about X to about Y.”

As used herein, the term “sub-epidermal moisture” or “SEM” refers to theincrease in tissue fluid and local edema caused by vascular leakinessand other changes that modify the underlying structure of the damagedtissue in the presence of continued pressure on tissue, apoptosis,necrosis, and the inflammatory process.

As used herein, a “system” may be a collection of devices in wired orwireless communication with each other.

As used herein, “interrogate” refers to the use of radiofrequency energyto penetrate into a patient’s skin.

As used herein, a “patient” may be a human or animal subject.

As used herein, “healthy” may describes tissue that does not exhibitsymptoms of damage to cellular walls or blood vessels, where thepresence of an increased amount of ECF is an indication of such damage.

As used herein, “extracellular fluid” or “ECF” refers to bodily fluidcontained outside of cells, including plasma, interstitial fluid, andtranscellular fluid.

As used herein, “susceptible to formation of a diabetic foot ulcer” maydescribe tissue that exhibit symptoms of damage to cellular walls orblood vessels, such as edema or an increased amount of ECF, yet no openulcer is present.

As used herein, “time_0” refers to an initial time point, for example,when an open ulcer is first detected.

As used herein, “time_1” refers to a time point later than time_0.

As used herein, “time_2” refers to a time point later than time_1.

FIG. 1A is a side view of a portion of the anatomy of a foot 20. Theareas of the foot that are most likely to develop a diabetic foot ulcerare the heel, located below the calcaneus bone 21, and the pad of thefoot, located under the metatarsal bone 22.

FIG. 1B is an enlarged view of the area “A” of FIG. 1A. The ends of themetatarsal bone 22 and the adjoining phalange bone 23 are shown inproximity to the skin 24 of the sole of the foot 20. A portion of thebody weight of the patient creates a compressive force 30 applied by themetatarsal bone 22 to the tissue in region 40. Force 30 is opposed byresistive force 36 applied by the floor to the skin 24 under region 40to support the patient. Muscular activity by the patient, for examplewalking or simply balancing on their feet while standing, creates shearforce 32 between the metatarsal bone 22 and tissue 40 as well as theresisting shear force 38 between the floor and the skin 24. Thus, thetissue in region 40 is simultaneously subject to both compression andshear forces.

It has been observed that a healthy patient will shift their weight fromfoot to foot as well as shift their center of mass relative to theirfeet while standing stationary. This limits the duration of time duringwhich forces are applied to any particular region of tissue. Peripheralneuropathy, however, reduces the sensation in the tissue that is createdby the patient’s weight and, therefore, reduces the unconscious shiftingof their weight and patients suffering from peripheral neuropathy areobserved to lack the normal motion while standing. This leads toextended period of time of continuous compressive force being applied tolocal areas of tissue, such as region 40. This extended exposure tomoderate levels of force is thought to contribute to the formation ofulcers in these areas.

FIGS. 2A, 2B, 2C, and 2D depict the conditions and progression of anopen ulcer. FIG. 2A depicts an initial open ulcer 50A at time_0. Theulcer 50A is surrounded by a ring of increased pressure 52A.

FIG. 2B shows the pressure profile created in the condition of FIG. 2A.The force applied by the floor, or by a shoe worn by the patient, isapplied as a locally uniform pressure 56 to the skin 24 of the foot 20.The applied pressure 56 is opposed internally by forces 53. No pressurecan be applied over the ulcer 50, as the tissue has sloughed away. Thus,the internal forces in the toroidal region 52A increase to a peak 54 topick up the force that would have been applied to the ulcer 50. Thispeak force 54 is high enough to cause further tissue damage in the ring52A. A callus will commonly form over the region 52A as the bodyattempts to protect itself from the increased pressure. The tissue belowthe callus, however, is still being damaged and will exhibit an increasein ECF.

FIG. 2C depicts the same region of tissue at time_1 that is subsequentto time_0. The increased level of pressure in region 52A led to tissuedeath in region 52A and the tissue in region 52 has sloughed away sothat the ulcer 50B is larger than the prior ulcer 50A. The appliedpressure 56 has not changed, however, so now the tissue in the region52B around the larger ulcer 50B must pick up even more force. Thisaccelerates the expansion of the ulcer 50 as the tissue in are region52B dies quicker under the higher applied load.

FIG. 2D depicts the same region of tissue as FIGS. 2A and 2C, now attime_2 that is subsequent to time_1. The ulcer 50 has grown to size 50Cand the region 52C of increased pressure is large than the prior regions52A, 52B.

In the situation shown in FIG. 2A, where an ulcer has formed,interventional therapies will be introduced to prevent the growth of theulcer 50 and allow the body to heal the open ulcer 50. Therapies mayinvolve placing pressure-relieving pads around the ulcer to spread thepressure 56 over a larger region of healthy tissue and eliminate thepeak 54 that leads to further damage. Determining whether the therapy isworking, however, is only possible by observation over time that theulcer is not progressing.

FIG. 3A discloses a toroidal bioimpedance sensor 90. In this exemplaryconfiguration, a center electrode 110 is surrounded by a ring electrode120. Without being limited to a particular theory, the gap between thetwo electrodes affects the depth of field penetration into the substratebelow sensor 90. In one aspect, a ground plane (not visible in FIG. 3A),is parallel to and separate from the plane of the electrodes and, in anaspect, extends beyond the outer diameter of ring electrode 120. Withoutbeing limited to a particular theory, a ground plane may limit the fieldbetween electrodes 110 and 120 to a single side of the plane ofelectrodes 110 and 120 that is on the opposite side of the plane ofelectrodes 110 and 120 from the ground plane.

FIG. 3B discloses an idealized field map created by a toroidal sensor ofFIG. 3A when activated by a drive circuit (not shown in FIG. 3B). Whenan electric voltage is applied across electrodes 110 and 120, anelectric field 140 is generated between electrodes 110 and 120 thatextends outward from the plane of electrodes 110 and 120 to a depth offield 150. The diameter of center electrode 110, the inner and outerdiameters of ring electrode 120, and the gap between electrodes 110 and120 may be varied to change characteristics of the field 140, forexample the depth of field 150.

In use, a drive circuit can measure an electrical property or parameterthat comprises one or more electrical characteristics selected from thegroup consisting of a resistance, a capacitance, an inductance, animpedance, a reluctance, and other electrical characteristics as sensedby electric field 140. Depending on the type of drive circuit beingemployed in an apparatus, a sensor of an apparatus may be a bipolarradiofrequency sensor, a bioimpedance sensor, a capacitive sensor, or anSEM sensor. In an aspect, a measured electrical parameter is related tothe moisture content of the epidermis of a patient at a depth that isdetermined by the geometry of electrodes 110 and 120, the frequency andstrength of electrical field 140, and other operating characteristics ofthe apparatus drive circuit. In one aspect, a measured moisture contentis equivalent to the SEM content with a value on a predetermined scale.In an aspect, a predetermined scale may range from 0 to 20, such as from0 to 1, from 0 to 2, from 0 to 3, from 0 to 4, from 0 to 5, from 0 to 6,from 0 to 7, from 0 to 8, from 0 to 9, from 0 to 10, from 0 to 11, from0 to 12, from 0 to 13, from 0 to 14, from 0 to 15, from 0 to 16, from 0to 17, from 0 to 18, from 0 to 19. In one aspect, a predetermined scaledcan be scaled by a factor or a multiple based on the values providedherein. In an aspect, multiple measurements are taken while varying oneor more of these operating characteristics between readings, therebyproviding information related to the moisture content at various depthsof the skin.

One or more regions may be defined on a body. In an aspect, measurementsmade within a region are considered comparable to each other. A regionmay be defined as an area on the skin of the body wherein measurementsmay be taken at any point within the area. In an aspect, a regioncorresponds to an anatomical region (e.g., heel, ankle, lower back). Inan aspect, a region may be defined as a set of two or more specificpoints relative to anatomical features wherein measurements are takenonly at the specific points. In an aspect, a region may comprise aplurality of non-contiguous areas on the body. In an aspect, the set ofspecific locations may include points in multiple non-contiguous areas.

In an aspect, a region is defined by surface area. In an aspect, aregion may be, for example, between 5 and 200 cm², between 5 and 100cm², between 5 and 50 cm², or between 10 and 50 cm², between 10 and 25cm², or between 5 and 25 cm².

In an aspect, measurements may be made in a specific pattern or portionthereof. In an aspect, the pattern of readings is made in a pattern withthe target area of concern in the center. In an aspect, measurements aremade in one or more circular patterns of increasing or decreasing size,T-shaped patterns, a set of specific locations, or randomly across atissue or region. In an aspect, a pattern may be located on the body bydefining a first measurement location of the pattern with respect to ananatomical feature with the remaining measurement locations of thepattern defined as offsets from the first measurement position.

In an aspect, a plurality of measurements are taken across a tissue orregion and the difference between the lowest measurement value and thehighest measurement value of the plurality of measurements is recordedas a delta value of that plurality of measurements. In an aspect, 3 ormore, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more,or 10 or more measurements are taken across a tissue or region.

In an aspect, a threshold may be established for at least one region. Inan aspect, a threshold of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, orother value may be established for the at least one region. In anaspect, a delta value is identified as significant when the delta valueof a plurality of measurements taken within a region meets or exceeds athreshold associated with that region. In an aspect, each of a pluralityof regions has a different threshold. In an aspect, two or more regionsmay have a common threshold.

In an aspect, a threshold has both a delta value component and achronological component, wherein a delta value is identified assignificant when the delta value is greater than a predeterminednumerical value for a predetermined portion of a time interval. In anaspect, the predetermined portion of a time interval is defined as aminimum of X days wherein a plurality of measurements taken that dayproduces a delta value greater than or equal to the predeterminednumerical value within a total of Y contiguous days of measurement. Inan aspect, the predetermined portion of a time interval may be definedas 1, 2, 3, 4, or 5 consecutive days on which a plurality ofmeasurements taken that day produces a delta value that is greater thanor equal to the predetermined numerical value. In an aspect, thepredetermined portion of a time interval may be defined as some portionof a different specific time period (weeks, month, hours etc.).

In an aspect, a threshold has a trending aspect wherein changes in thedelta values of consecutive pluralities of measurements are compared toeach other. In an aspect, a trending threshold is defined as apredetermined change in delta value over a predetermined length of time,wherein a determination that the threshold has been met or exceeded issignificant. In an aspect, a determination of significance will cause analert to be issued. In an aspect, a trend line may be computed from aportion of the individual measurements of the consecutive pluralities ofmeasurements. In an aspect, a trend line may be computed from a portionof the delta values of the consecutive pluralities of measurements.

In an aspect, the number of measurements taken within a single regionmay be less than the number of measurement locations defined in apattern. In an aspect, a delta value will be calculated after apredetermined initial number of readings, which is less than the numberof measurement locations defined in a pattern, have been taken in aregion and after each additional reading in the same region, whereinadditional readings are not taken once the delta value meets or exceedsthe threshold associated with that region.

In an aspect, the number of measurements taken within a single regionmay exceed the number of measurement locations defined in a pattern. Inan aspect, a delta value will be calculated after each additionalreading.

In an aspect, a quality metric may be generated for each plurality ofmeasurements. In an aspect, this quality metric is chosen to assess therepeatability of the measurements. In an aspect, this quality metric ischosen to assess the skill of the clinician that took the measurements.In an aspect, the quality metric may include one or more statisticalparameters, for example an average, a mean, or a standard deviation. Inan aspect, the quality metric may include one or more of a comparison ofindividual measurements to a predefined range. In an aspect, the qualitymetric may include comparison of the individual measurements to apattern of values, for example comparison of the measurement values atpredefined locations to ranges associated with each predefined location.In an aspect, the quality metric may include determination of whichmeasurements are made over healthy tissue and one or more evaluations ofconsistency within this subset of “healthy” measurements, for example arange, a standard deviation, or other parameter.

In one aspect, a measurement, for example, a threshold value, isdetermined by SEM Scanner Model 200 (Bruin Biometrics, LLC, Los Angeles,CA). In another aspect, a measurement is determined by another SEMscanner.

In an aspect, a measurement value is based on a capacitance measurementby reference to a reference device. In an aspect, a capacitancemeasurement can depend on the location and other aspects of anyelectrode in a device. Such variations can be compared to a referenceSEM device such as an SEM Scanner Model 200 (Bruin Biometrics, LLC, LosAngeles, CA). A person of ordinary skill in the art understands that themeasurements set forth herein can be adjusted to accommodate adifference capacitance range by reference to a reference device.

FIG. 3C provides top and bottom views of a SEM scanner 170 that containselectronics that drive sensor 174, which is similar to sensor 90 of FIG.3A, and measure a capacitance between electrodes 110 and 120. Thiscapacitance may be converted to a SEM value that is displayed on display176.

Aspects of sensor 90 and SEM scanner 170 are disclosed in WO2016/172263, from which the U.S. Pat. Application Serial No. 15/134,110was filed as a national phase entry, all of which are incorporated byreference herein in their entireties.

FIG. 4 depicts an exemplary electrode array 290, according to thepresent disclosure. Array 290 is composed of individual electrodes 300disposed, in this example, in a regular pattern over a substrate 292. Inan aspect, each electrode 300 is separately coupled (through conductiveelements not shown in FIG. 4 ) to a circuit (not shown in FIG. 4 ) thatis configured to measure an electrical parameter. In one aspect, a“virtual sensor” is created by selective connection of predeterminedsubsets of electrodes 300 to a common element of a circuit. In thisexample, a particular electrode 310 is connected as a center electrode,similar to electrode 110 of FIG. 3A, and six electrodes 320A-320F areconnected together as a “virtual ring” electrode, similar to electrode120 of FIG. 3A. In an aspect, two individual electrodes are individuallyconnected to the circuit to form a virtual sensor, for exampleelectrodes 310 and 320A are respectively connected as the two electrodesof a sensor. In one aspect, one or more electrodes 300 are connectedtogether to form one or the other of the electrodes of a two-electrodesensor.

Any pair of electrodes, whether composed of single electrodes or a setof electrodes coupled together to form virtual electrodes, is coupled toelectronics (not shown in FIG. 4 ) that are configured to measures anelectrical property or parameter that comprises one or more of aresistance, a capacitance, an inductance, an impedance, a reluctance, orother electrical characteristic with one or more of sensors 90, 174,290, 430, 440, or other two-electrode sensor. Electronics of the presentdisclosure may be further configured to compare the measured firstcapacitance to a reference value and providing a signal if the measuredcapacitance differs from the reference value by an amount greater than athreshold. In an aspect, one or both of the reference value and thethreshold are predetermined.

FIG. 5 depicts another exemplary array 400 of electrodes 410, accordingto the present disclosure. In this non-limiting example, each of theelectrodes 410 is an approximate hexagon that is separated from each ofthe surrounding electrodes 410 by a gap 420. In one aspect, electrodes410 are one of circles, squares, pentagons, or other regular orirregular shapes. In an aspect, gap 420 is uniform between allelectrodes 410. In one aspect, gap 420 varies between variouselectrodes. In one aspect, gap 420 has a width that is narrower than thecross-section of each of the electrodes 410. Electrodes 410 may beinterconnected to form virtual sensors as described below with respectto FIGS. 6A-6B and 10A-10C.

FIG. 6A depicts an array 400 of electrodes 410 that are configured, e.g.connected to a measurement circuit, to form an exemplary sensor 430,according to the present disclosure. A single hexagonal electrode 410that is labeled with a “1” forms a center electrode and a ring ofelectrodes 410 that are marked with a “2” are interconnected to form aring electrode. In an aspect, electrodes 410 between the center and ringelectrode are electrically “floating.” In one aspect, electrodes 410between the center and ring electrode are grounded or connected to afloating ground. In an aspect, electrodes 410 that are outside the ringelectrode are electrically “floating.” In one aspect, electrodes 410that are outside a virtual ring electrode are grounded or connected to afloating ground.

FIG. 6B depicts an alternate aspect where an array 400 of electrodes 410has been configured to form a virtual sensor 440, according to thepresent disclosure. In an aspect, multiple electrodes 410, indicated bya “1,” are interconnected to form a center electrode while a double-widering of electrodes, indicated by a “2,” are interconnected to form aring electrode. In one aspect, various numbers and positions ofelectrodes 410 are interconnected to form virtual electrodes of avariety of sizes and shapes.

FIGS. 6A and 6B depict an exemplary configuration of an electrode array400 that is capable of forming sensors 430 in multiple overlappinglocations, according to the present disclosure. In FIG. 6A, a virtualsensor 430A has been formed with center electrode 432 formed by a singleelectrode 410, indicated by a “1,” and a ring electrode 434 formed by aplurality of electrodes 410, indicated by a “2.” This same array 400 isshown in FIG. 6B, where a new virtual sensor 430B has been formed with acenter electrode 436, indicated by a “3,” and ring electrode 438,indicated by a “4.” The position of virtual sensor 430A is shown by thedark outline. It can be seen that virtual sensor 430B overlaps theposition of virtual sensor 430A, this allowing measurements to be madeat a finer resolution than the diameter of sensors 430.

FIG. 6E shows how sensors 430 may be formed from an array of electrodes400 that is larger than the portion of a patient’s skin that is beingpositioned against the array, according to the present disclosure. Inthis example, the outline of contact area 450 of sole 22R of a rightfoot of a patient, as seen from underneath the foot, is shown overlaidon array 400. In this example, sensor 430C has been formed in a locationwhere a portion of sensor 430C extends beyond the edge of contact area450. In such a position, the capacitance or other electrical parametermeasured by sensor 430C is lower than the capacitance measured by sensor430D, which is positioned completely within contact area 450. It can beseen that a sensor 430 may be formed at any point within array 400 and,depending on the position of sensor 430, may partially overlap thecontact area at any level within the range of 0-100%.

In an aspect, two sensors may overlap 0-50%, such as 0-10%, 5-15%,10-20%, 15-25%, 20-30%, 25-35%, 30-40%, 35%-45%, 40-50%, 0-25%, 15-35%,or 25-50%. In one aspect, two sensors may overlap 25-75%, such as25-35%, 30-40%, 35%-45%, 40-50%, 45-55%, 50-60%, 55-65%, 60-70%, 65-75%,25-50%, 40-55%, or 50-75%. In one aspect, two sensors may overlap50-100%, such as 50-60%, 55-65%, 60-70%, 65-75%, 70-80%, 75%-85%,80-90%, 85-95%, 90-100%, 50-75%, 65-85%, or 75-100%.

In one aspect, an array of sensors 400 may further comprise a pluralityof contact sensors (not shown on FIG. 6E) on the same planar surface as,and surrounding, each of the electrodes to ensure complete contact ofthe one or more virtual sensors to the skin surface. The plurality ofcontact sensors may be a plurality of pressure sensors, a plurality oflight sensors, a plurality of temperature sensors, a plurality of pHsensors, a plurality of perspiration sensors, a plurality of ultrasonicsensors, a plurality of bone growth stimulator sensors, or a pluralityof a combination of these sensors. In some embodiments, the plurality ofcontact sensors may comprise four, five, six, seven, eight, nine, or tenor more contact sensors surrounding each electrode.

FIGS. 6F and 6G depict an example of how comparison of SEM valuesassociated with sensors in known relative locations can identifybisymmetric locations, according to the present disclosure. In thisexample, sensors 430 are formed at non-overlapping locations, marked “A”to “H” in FIG. 6F, across a contact area 450R of a right foot 20R. TheSEM values measured at each location are plotted in the graph of FIG.6G. In this example, the SEM value of locations “A” and “H” are low orzero, reflecting the non-overlap of sensor 430 with contact area 450 inthose locations. The SEM values associated with locations “B” and “G”are higher, as sensor 430 overlaps a portion of contact area 450 inthose positions. The SEM values for locations C-D-E-F are higher and, inthis example, approximately the same, indicating that sensor 430 wascompletely within contact area 450 at those locations. In an aspect, anSEM measurement apparatus such as apparatus 180 may determine thatcertain locations, for example locations “C” and “F,” are bisymmetricwith respect to a centerline 452R of right foot 20R. In one aspect,where a similar set of measurements is made at locations A′-H′ on a leftfoot 20L, a location on each foot 20L and 20R, for example locations Eand E′, may be determined to be approximately bisymmetric.

FIG. 7A depicts an exemplary mat assembly 500 that incorporates aplurality of bioimpedance sensors 520, according to the presentdisclosure. Although sensors 520 are shown as toroidal sensors similarto sensors 90 depicted in FIG. 3A, sensors 520 may be any configurationof electrical measurement sensor, including the configurations shown inFIGS. 4, 5, and 6A-6B. Sensors 520 are distributed across substrate 510.In an aspect, a portion of substrate 510 is flexible. In one aspect, aportion of substrate 510 is rigid. In an aspect, electrodes of sensor520 are electrically bare, thereby allowing conductive electricalcontact with a patient’s foot when a patient stands on mat assembly 500.In one aspect, electrodes of sensor 520 are electrically insulated, forexample by an insulating cover layer (not shown in FIG. 7A), therebyallowing only capacitive electrical contact with a patient’s foot when apatient stands on mat assembly 500.

In an aspect, mat assembly 500 comprises one of more temperature sensors(not shown in FIG. 7A), that detect the temperature of one or morelocations on a foot. In one aspect, a temperature sensor is co-locatedwith SEM sensor 520 so as to provide temperature and SEM measurements ofa common location.

In one aspect of mat assembly 500, a signal is provided when themeasured capacitance differs from a reference capacitance value by anamount greater than a first threshold and the measured temperaturediffers from a temperature reference value by an amount greater than asecond threshold. In an aspect, one or both of the thresholds arepredetermined. In one aspect, a first threshold is set at thecorresponding reference capacitance value plus at least 5%, such as atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 100%, at least 150%, atleast 200%, at least 250%, at least 300%, at least 400%, or at least500%. In one aspect, a second threshold is set at the correspondingreference temperature value plus at least 5%, such as at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, at least 100%, at least 150%, at least 200%, atleast 250%, at least 300%, at least 400%, or at least 500%. In oneaspect, one or both of the capacitance and temperature reference valuesare determined from prior measurements, for example a rolling average ofthe past 5 sequential measurements or by an average of multiplemeasurements made in an earlier time period, e.g. a month earlier.

In one aspect, one or both of the capacitance and temperature referencevalues are determined from measurements made when the tissue was in aknown healthy state, for example while in a doctor’s office when aclinician has made an examination of the tissue and determined that thetissue is healthy, i.e. not susceptible to the formation of a diabeticfoot ulcer.

FIG. 7B depicts another exemplary mat assembly 502 that comprises arrays530L and 530R of electrical sensors 520, where arrays 530L and 530R aredisposed so as to underlie the left and right feet, respectively, of apatient while standing on mat assembly 502. In an aspect, outlines 540Land 540R of the left and right feet are drawn over arrays 530L and 530Rso as to guide the patient to stand in the proper location.

FIG. 7C depicts an aspect of a mat assembly 504 that has one or moresensors 520 disposed within each of the outlines 540L and 540R. In anaspect, a sensors 520A is located in a position corresponding toportions of the foot that are most likely to develop an ulcer, forexample the ball of a foot. In one aspect, sensors 520B may be locatedunder the heel or other locations of a foot.

In one aspect, substrate 510 is partially transparent and mat 504comprises a second substrate 512 on which are mounted one or moreoptical sensors 550. In an aspect, optical sensor 550 is a cameracapable of imaging the underside of a foot of a patient standing on mat504. In one aspect, optical sensor 550 is sensitive to visible light. Inan aspect, optical sensor 550 is sensitive to infrared light.

The use of mat assemblies 500, 502, 504 and the like on a regular basisby patients can serve to detect changes in the health of their feet. Forexample, a baseline will be established by measurement of electricalcharacteristics, such as capacitance, of each foot at the time ofexamination by a clinician who verifies that there is no ulcer orindication of damage that would lead to formation of an ulcer in apatient. The patient then places the mat 500, 502, 504 in a readilyaccessible location in their home, for example in front of the bathroomsink. On a regular basis, such as daily while brushing their teeth, thepatient triggers a measurement of their feet by the sensors 520. If thepatient is standing on the same location, for example being guided byoutlines 540L and 540R, then each sensor 520 and 550 is measuring thesame position for each repeated measurement. In an aspect, a temperaturemeasurement is made by an infrared sensor 550 or one of more temperaturesensors (not shown in FIG. 7C) in mat assembly 500, 502, 504. In oneaspect, an image is captured by an optical sensor 550 in mat assembly504. This information is stored in a local memory or transmitted to aremote storage location, such as the doctor’s office. Each dailymeasurement is compared to reference derived from previous measurements,for example a measurement made in a clinician’s office or an average oflast week’s measurements. If the most recent measurement deviates fromthe reference, the patient is informed of the deviation. The patient canthen consult a clinician for further evaluation and possibleintervention. In an aspect, a change in the measured SEM value largerthan the threshold triggers a notification. In one aspect, a change inthe measured SEM value larger than a first threshold and a change in themeasured temperature larger than a second threshold together trigger anotification. In an aspect, either a change in the measured SEM valuelarger than a first threshold or a change in the measured temperaturelarger than a second threshold triggers a notification. In one aspect, afirst threshold is set at the corresponding reference SEM value plus atleast 5%, such as at least 10%, at least 15%, at least 20%, at least25%, at least 30%, at least 35%, at least 40%, at least 45%, at least50%, at least 55%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90%, at least 95%, at least100%, at least 150%, at least 200%, at least 250%, at least 300%, atleast 400%, or at least 500%. In one aspect, a second threshold is setat the corresponding reference temperature value plus at least 5%, suchas at least 10%, at least 15%, at least 20%, at least 25%, at least 30%,at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 100%, at least 150%, atleast 200%, at least 250%, at least 300%, at least 400%, or at least500%. In an aspect, information such as an image of the underside of apatient’s foot is always sent to a clinician for review.

In an aspect, measurements of the left and right foot are compared toeach other. For example, with reference to FIGS. 6F and 6G, locations Eand E′ are compared to each other. In one aspect, a difference betweenthe left and right measurements is compared to a reference and thepatient notified if the difference exceeds a threshold.

FIG. 8A discloses a foot cover 600 that incorporates bioimpedancesensors 520 as shown in the cut-away view of FIG. 8B, according to thepresent disclosure. In an aspect, foot cover 600 comprises a sock orother flexible, conforming garment 610 into which a foot can beinserted. In one aspect, a flexible, conforming garment 610 may be aflexible shoe, similar to a “water shoe,” made from a flexible, elasticmaterial such as rubber. In an aspect, a flexible, conforming garment610 may be a conventional shoe, for example a leather dress shoe or asneaker. Sensors 520 are located in one or more locations thatcorrespond to areas of concern for development of ulcers. In one aspect,sensors 520 are located under or around the heel of a flexible,conforming garment 610. In an aspect, sensors 520 are located on thesole of a flexible, conforming garment 610. In one aspect, sensors 520are located in the area around the toes (not visible in FIG. 8B) of aflexible, conforming garment 610.

FIG. 9 discloses a sandal 650 that incorporates bioimpedance sensors520, according to the present disclosure. One or more sensors 520 aredisposed on a sandal in locations that correspond to areas of potentialulcer development.

FIGS. 10A, 10B, and 10C depict configurations of addressable electrodesof FIG. 5 that vary the performance capabilities of a sensor, accordingto the present disclosure. FIG. 10A depicts an exemplary firstconfiguration 700, where electrodes 710 are connected so as to form acenter electrode 720 and a ring electrode 730, similar to electrodes ofFIGS. 6A and 6B. Sensor configuration 700 has a gap 740 of a single rowof electrodes 710, which results in a first field depth 150, withreference to FIG. 3B.

FIG. 10B depicts a second exemplary configuration 702 of the same arrayof sensors 710, where one electrode is connected to form a centerelectrode 722 while a plurality of electrodes 710 are connected to forma ring electrode 732 that is larger in diameter than ring electrode 730and having a gap 742 that is larger than gap 740. Sensor configuration702 will have a second field depth 150 that is larger than that ofsensor configuration 700.

FIG. 10C depicts a third exemplary configuration 704 of the same arrayof sensors 710, where one electrode is connected to form a centerelectrode 724 while a plurality of electrodes 710 are connected to forma ring electrode 734 that is larger in diameter than ring electrodes 730and 732 and having a gap 744 that is larger than gaps 740 and 742.Sensor configuration 704 will have a third field depth 150 that islarger than either of sensor configurations 700 or 702.

In an aspect, a mat assembly 500 comprises an array of electrodes 710distributed across a portion of substrate 510. At a location of an arraythat corresponds to an area of concern on a patient’s foot, mat assembly500 is configured to form a sensor configuration 700 and make a firstmeasurement, then reconfigure electrodes 710 to form a sensorconfiguration 702 and make a second measurement. The first and secondmeasurements provide information about the difference in ECF atdifferent depths below the skin of a foot, thereby providing improvedknowledge of the tissue condition within the foot. In one aspect, matassembly 500 is configured to then form a sensor configuration 704 andtake a third measurement. Comparison of the three measurements provideseven greater resolution of the internal tissue condition.

FIGS. 11A and 11B depict an exemplary aspect of a sensor assembly 500configured to be placed in a known position on a patient’s skin,according to the present disclosure. In this example, sensor assembly500 has a shaped substrate 510 that is configured to conform toposterior and bottom surfaces of the heel of a foot 20. In one aspect,shaped substrate 510 is suitable for use with both a left foot 20L and aright foot 20R. Sensor assembly 500 comprises one or more sensors 520disposed on the inner surface of shaped substrate 510. In this example,sensors 520 are configured as toroidal sensors as shown in FIG. 1A. Inan aspect, the inner surface of shaped substrate 510 is lined with anarray 400 of electrodes 410, with reference to FIG. 5 , such thatvirtual sensors may be formed at any location. In one aspect, sensors ofother shapes and configurations are provided on the inner surface ofshaped substrate 510. In an aspect, shaped substrate 510 is a flexiblepanel (not shown in FIG. 11A) that can be conformed to a patient’s skin,for example wrapped around the back of an ankle. In one aspect, sensorassembly 500 comprises a cable 530 to connect sensors 520 to one or moreof a power source, a circuit configured to measure one or more ofcapacitance or other electrical property, a processor, a communicationsubsystem, or other type of electronic assembly (not shown in FIG. 11A).

FIG. 11B depicts an exemplary configuration of sensor assembly 500 wheremultiple sensors 520 disposed on shaped substrate 510 such that, forexample when sensor assembly 500 is placed against the skin of a patientaround the back, sides, and bottom of the right heel center. Thisenables multiple SEM measurements to be taken in repeatable location onthe heel with sensor assembly 500 in a single position. In one aspect(not shown in FIGS. 11A and 11B), sensor assembly 500 is configured tobe placed on a portion of the back of a patient thus providing thecapability to make measurements at bisymmetric locations on the back. Inan aspect, shaped substrate 510 is configured to match anatomicalfeatures of the target area of a patient. In one aspect, shapedsubstrate 510 comprises markings or other indicators that can be alignedwith features of a patient’s body, so as to enable measurements to betaken at the same location at time intervals over a period of time inthe general range of hours to weeks. In one aspect, sensor assembly 500is integrated into a lining of a garment or shoe or other article ofclothing. In an aspect, sensor assembly 500 is integrated into a sheet,blanket, liner, or other type of bed clothing. In one aspect, sensorassembly 500 comprises a wireless communication capability, for examplea passive radio frequency identification (RFID) or an inductivecoupling, to allow actuation of sensors 520 without physicallyconnecting to sensor assembly 500.

In an aspect, sensors 520 are coupled to electronics (not shown in FIG.11B) that are configured to compare a current set of measurements toeach other and to past measurements made in the same location. In anaspect, electronics of the present disclosure may provide a signal ifone or more of certain conditions are met. Such conditions may include,but are not limited to, a change in the difference between measurementsmade at two locations when compared to the difference in measurementsmade at the same two locations at a previous time, and a change in themeasured value at a particular location from prior measurements at thesame location that is greater than a threshold amount.

FIG. 12 depicts a schematic depiction of an integrated system 800 formeasurement, evaluation, storage, and transfer of SEM values, accordingto the present disclosure. In this example, system 800 comprises a SEMmeasurement apparatus 810, for example a SEM scanner 170, that comprisesthe capability to wirelessly communicate with a WiFi access point 820.Apparatus 810 communicates with one or more of a SEM application runningon a server 850, an application running on a laptop computer 840, a“smart phone” 830, or other digital device. In an aspect, laptopcomputer 840 and smart phone 830 are carried by the user of apparatus810, for example a nurse, and the application provides feedback andinformation to the user. In an aspect, information received fromapparatus 180 for a patient is stored in a database 850. In one aspect,information received from apparatus 810 for a patient is stored in adatabase 860. In an aspect, information received from apparatus 810 istransferred over a network 855 to another server 880 that stores aportion of the information in an electronic medical record (EMR) 870 ofthe patient. In one aspect, information from apparatus 810 or retrievedfrom database 860 or EMR 870 is transferred to an external server 890and then to a computer 895, for example a computer at the office of adoctor who is proving care for the patient.

In an aspect, apparatus 810 is one of a mat assembly 500, a foot cover600, or other measurement device and one or both of smart phone 830 andlaptop 840 are used by the patient to receive information andnotifications related to measurements made by mat assembly 500.

FIG. 13 depicts a sensing band 550, according to the present disclosure.In one aspect, a SEM sensor as described herein, for example sensor 90or sensor 400, is embedded in a band 554 that can be wrapped around acalf 60 as shown in FIG. 13 . In an aspect, band 554 comprises sensorsconfigured to measure one or more of oxygenation of the tissue, whichmay comprise measurement of one or both of oxyhemoglobin anddeoxyhemoglobin, temperature of one or more points on the skin, pulserate, blood volume and blood pressure. In one aspect, the combination ofmeasurements made by band 554 provides information regarding the flow ofblood to the foot, where reduced blood flow is a possible indication ofsusceptibility to formation of DFUs. In an aspect, this informationcomprises measurement of blood volume and refill times on the portion ofthe calf 60 that is proximate to band 554.

FIG. 14A depicts an integrated sensor and stimulator assembly 201suitable for treatment of a pressure ulcer, according to the presentdisclosure. In an aspect, an integrated sensor and stimulator assembly201 is provided to a patient in need thereof. Assembly 201 has asubstrate 210 with a plurality of sensors 90 disposed on a firstsurface. Sensors 90 are configured to measure sub-epidermal moisture(SEM) as an indication of tissue health at the location of therespective sensor 90. In an aspect, there are two electrodes 212A and212B that are in conductive contact with the skin of a patient (notshown in FIG. 14A) when the assembly 201 is placed on the skin. Theseelectrodes 212A, 212B are connected to an external controller (not shownin FIG. 14A) that is configured to apply a therapeutic electricalstimulus to the tissue between the electrodes 212A, 212B, with thestimulus applied for periods having a time duration and a time intervalbetween the periods. In an aspect, low level voltage and/or currents mayenhance the healing of a pressure ulcer. Sensors 90 are individuallyconnected to an external controller (not shown in FIG. 14A) that isconfigured to measure the capacitance of the respective sensors 90. Inan aspect, the capacitance is measured in a time interval between thestimulus periods. In one aspect, a time interval can be in the generalrange of hours to weeks. In an aspect, assembly 201 comprises anabsorbent pad and a non-stick layer (not shown in FIG. 14A) overlaidupon sensors 90 and electrodes 212A, 212B. In an aspect, assembly 201comprises a layer of adhesive (not shown in FIG. 14A) overlaid upon aportion of substrate 210 so as to allow assembly 201 to be adhesivelyattached to the skin of a patient. In an aspect, substrate 201 may bepermeable to gas while impervious to fluid.

The combination of a standard bandage (the absorbent pad, non-sticklayer, and covering substrate) with a therapeutic instrument, such aselectrodes 212A, 212B and the associated external controller, with oneor more sensors 90 provides a means of protecting the wound, improvingthe healing process, and monitoring the healing without disturbing theassembly 201.

FIG. 14B depicts the sole of a foot 20 of a patient having a pressureulcer 205.

FIG. 14C depicts an assembly 201 adhered to the sole of foot 20 over thepressure ulcer 205. In an aspect, assembly 201 is placed over ulcer 205and left in place for several days. In an aspect, assembly 201 comprisesa toroidal pad that relieves the pressure on the pressure ulcer 205. Theexternal controller of electrodes 212A, 212B is periodically attached toelectrodes 212A, 212B to apply a therapeutic stimulus. During theinterval between these stimuli, the external controller of the sensors90 is attached to one or more of the sensors 90 to make a SEMmeasurement.

In an aspect, assembly 201 comprises a battery and wirelesscommunication capability that enables the external controller to causethe stimulus to be applied through electrodes 212A, 212B without a wiredconnection to the assembly. Similarly, the assembly may be configured toallow the external controller to communicate with the sensors 90 to makeand receive SEM measurements without a wired connection. In an aspect,the assembly 201 comprises a microcontroller configured to apply thetherapeutic stimulus and make SEM measurements and wirelessly transmitinformation, such as the SEM values.

It will be apparent to those of ordinary skill in the art that theconcept of combining therapeutic instruments and SEM sensors can beapplied to other types of wounds and to other locations on the bodybesides the sole of the foot, such as an ankle, or a bony prominence.

FIG. 14D depicts a bandage assembly 202 adapted for placement over apressure ulcer on the sacrum of a patient in need thereof. The assembly202 comprises substrate 220 that is porous to gas while impervious tofluid. The assembly 202 comprises a pad 222 (seen from the external sidein FIG. 14D) that provides both protective padding and absorption. Inthis example, a single sensor 90 is positioned on the underside of thepad 222 such that the sensor is directly over the pressure ulcer whenthe assembly is applied over an early-stage pressure ulcer with unbrokenskin. The electrodes 214A, 214B are location adjacent to the sensor 90and on the same underside so that they will be in contact with the skinof the patient. In this configuration, the assembly 202 can be placedover an early-stage ulcer and protect, improve the healing process, andmonitor the progress of the healing with removal of the assembly 202 ordisturbance of the wound.

Having now generally described the invention, the same will be morereadily understood through reference to the following examples that areprovided by way of illustration, and are not intended to be limiting ofthe present disclosure, unless specified.

EXAMPLES Example 1: Taking SEM Measurements at Multiple Locations of theFoot

SEM measurements were taken at the foot using one of three methods belowto ensure complete contact of an electrode with the skin of a humanpatient.

FIG. 15A illustrates a method used to take SEM measurements starting atthe posterior heel using an apparatus according to the presentdisclosure. First, the forefoot was dorsiflexed such that the toes werepointing towards the shin. Second, a bioimpedance sensor 1520 waspositioned at the base of the heel 1530. The electrode was adjusted forfull contact with the heel, and multiple SEM measurements were thentaken in a straight line towards the toes, including the ball of thefoot 1540. The ball of the foot is one of the primary locations ofdiabetic foot ulcer.

FIG. 15B illustrates a method used to take SEM measurements starting atthe lateral heel using an apparatus according to the present disclosure.First, the toes were pointed away from the body and rotated inwardtowards the medial side of the body. Second, an electrode was placed onthe lateral side of the heel 1550. A bioimpedance sensor 1520 wasadjusted for full contact with the heel, and multiple SEM measurementswere taken in a straight line towards the bottom of the foot. The ballof the foot 1540 is also shown in FIG. 15B.

FIG. 15C illustrates a method used to take SEM measurements starting atthe medial heel using an apparatus according to the present disclosure.First, the toes were pointed away from the body and rotated outwardstoward the lateral side of the body. Second, the electrode was placed onthe medial side of the heel 1560. A bioimpedance sensor 1520 wasadjusted for full contact with the heel, and multiple measurements weretaken around the back of the heel in a curve.

From the foregoing, it will be appreciated that the present inventioncan be embodied in various ways, which include but are not limited tothe following:

Embodiment 1. An apparatus for assessing susceptibility of tissue toformation of a diabetic foot ulcer, the apparatus comprising: aplurality of electrodes embedded on a substrate, where a pair of theelectrodes is capable of forming a capacitive sensor configured tomeasure a first capacitance of a first region of tissue proximate to thecapacitive sensor, a drive circuit electronically coupled to theelectrodes, a processor electronically coupled to the drive circuit, anda non-transitory computer-readable medium electronically coupled to theprocessor and comprising instructions stored thereon that, when executedon the processor, perform the steps of: receiving information regardingthe measured first capacitance from the drive circuit, comparing themeasured first capacitance to a first reference value, and providing asignal if the measured first capacitance differs from the firstreference value by an amount greater than a first predeterminedthreshold.

Embodiment 2. The apparatus of embodiment 1, where the first referencevalue is predetermined.

Embodiment 3. The apparatus of embodiment 1, where the first referencevalue is determined by measurement of the first capacitance at a timewhen the first region of tissue is healthy.

Embodiment 4. The apparatus of embodiment 1, where the first referencevalue is determined from measurements of the first capacitance at thefirst region of tissue one or more times prior to the most recentmeasurement of the first capacitance.

Embodiment 5. The apparatus of embodiment 1, where the first referencevalue is determined by a measurement from a bisymmetric location.

Embodiment 6. The apparatus of embodiment 1, where the first referencevalue is a measurement of a second capacitance of a second region oftissue that is separated from the first region of tissue.

Embodiment 7. The apparatus of embodiment 6, where the second region oftissue is known to be healthy.

Embodiment 8. The apparatus of embodiment 6, where the secondcapacitance is measured at approximately the same time as the firstcapacitance.

Embodiment 9. The apparatus of embodiment 1, the apparatus furthercomprising one or more temperature sensors that are configured tomeasure a temperature of the first region of tissue and are coupled tothe processor, where: the instructions further comprise: a step ofreceiving information regarding the measured temperature from the one ormore temperature sensors, and a step of comparing the measuredtemperature to a second reference value, and a step of providing asignal comprising providing the signal if the measured first capacitancediffers from the first reference value by an amount greater than thepredetermined first threshold and the measured temperature differs fromthe second reference value by an amount greater than a predeterminedsecond threshold.

Embodiment 10. The apparatus of embodiment 1, the apparatus furthercomprising one or more optical sensors configured to image an undersideof a foot of a patient while the patient is standing on the substrate.

Embodiment 11. A method for assessing susceptibility of tissue toformation of a diabetic foot ulcer, the method comprising: obtaining afirst capacitance value at a first location of a patient’s skin;obtaining a temperature measurement at the first location of a patient’sskin; and determining that the first location of a patient’s skin issusceptible to formation of a diabetic foot ulcer when the firstcapacitance value differs from a first reference value by an amountgreater than a first predetermined threshold and the temperaturemeasurement differs from a second reference value by an amount greaterthan a second predetermined threshold.

Embodiment 12. The method of embodiment 11, where the first referencevalue is predetermined.

Embodiment 13. The method of embodiment 11, where the first referencevalue is determined by measurement of the first capacitance at a timewhen the first location of a patient’s skin is healthy.

Embodiment 14. The method of embodiment 11, where the first referencevalue is determined from measurements of the first capacitance at thefirst location of a patient’s skin at one or more times prior to themost recent measurement of the first capacitance.

Embodiment 15. The method of embodiment 11, where the first referencevalue is a measurement of a second capacitance of a second location of apatient’s skin that is separated from the first location of a patient’sskin.

Embodiment 16. The method of embodiment 15, where the second region of apatient’s skin is known to be healthy.

Embodiment 17. The method of embodiment 15, where the second capacitanceis measured at approximately the same time as the first capacitance.

Embodiment 18. A method for assessing susceptibility of tissue toformation of a diabetic foot ulcer, the method comprising: obtaining afirst sub-epidermal moisture (SEM) value at a first location of apatient’s skin; obtaining a temperature measurement at the firstlocation of a patient’s skin; and determining that the first location ofa patient’s skin is susceptible to formation of a diabetic foot ulcerwhen the first SEM value differs from a first reference value by anamount greater than a first predetermined threshold and the temperaturemeasurement differs from a second reference value by an amount greaterthan a second predetermined threshold.

Embodiment 19. The method of embodiment 18, where the first referencevalue is predetermined.

Embodiment 20. The method of embodiment 18, where the first referencevalue is determined by measurement of the first SEM value at a time whenthe first location of a patient’s skin is healthy.

Embodiment 21. The method of embodiment 18, where the first referencevalue is determined from measurements of the first SEM value at thefirst location of a patient’s skin at one or more times prior to themost recent measurement of the first SEM value.

Embodiment 22. The method of embodiment 18, where the first referencevalue is a measurement of a second SEM value of a second location of apatient’s skin that is separated from the first location of a patient’sskin.

Embodiment 23. The method of embodiment 22, where the second location ofa patient’s skin is known to be healthy.

Embodiment 24. The method of embodiment 22, where the second SEM valueis measured at approximately the same time as the first SEM value.

Embodiment 25. An integrated apparatus for treating a diabetic footulcer in a patient in need thereof, the apparatus comprising: aplurality of sensors disposed on a flexible substrate, where theplurality of sensors are configured to measure sub-epidermal moisture(SEM) values at respective locations of the patient’s skin; twoelectrodes disposed on the flexible substrate; and an externalcontroller electrically connected to the two electrodes, where theexternal controller controls the two electrodes to detect conductivecontact with the patient’s skin during a SEM measurement period, and theexternal controller controls the two electrodes to apply a therapeuticstimulus to the patient during a therapeutic phase.

Embodiment 26. The apparatus of embodiment 25, further comprising anabsorbent pad.

Embodiment 27. The apparatus of embodiment 25, further comprising alayer of adhesive.

Embodiment 28. The apparatus of embodiment 25, where the flexiblesubstrate is permeable to gas while impervious to fluid.

Embodiment 29. An integrated apparatus for treating a diabetic footulcer in a patient in need thereof, the apparatus comprising: a sensorcomprising two electrodes disposed on a flexible substrate such that acurrent passing between the electrodes will pass through tissueproximate to a location of the patient’s skin; and an externalcontroller electrically connected to the two electrodes.

Embodiment 30. The integrated apparatus of embodiment 29, where theexternal controller controls the two electrodes to detect conductivecontact with the patient’s skin during a SEM measurement period, and theexternal controller controls the two electrodes to apply a therapeuticstimulus to the patient during a therapeutic phase.

While the invention has been described with reference to particularaspects, it will be understood by those skilled in the art that variouschanges may be made and equivalents may be substituted for elementsthereof without departing from the scope of the invention. In addition,many modifications may be made to a particular situation or material tothe teachings of the invention without departing from the scope of theinvention. Therefore, it is intended that the invention not be limitedto the particular aspects disclosed but that the invention will includeall aspects falling within the scope and spirit of the appended claims.

We claim:
 1. An apparatus for assessing susceptibility of tissue toformation of a diabetic foot ulcer (DFU), said apparatus comprising: aplurality of electrodes embedded on a substrate, wherein a pair of saidelectrodes is capable of forming a capacitive sensor configured tomeasure a first capacitance of a pre-selected first region of tissue ona first foot proximate to said capacitive sensor, wherein said measuredfirst capacitance corresponds to a level of extracellular fluid (ECF) atsaid pre-selected first region of tissue on said first foot, and whereinsaid pre-selected first region of tissue is selected from the groupconsisting of a calcaneal pad and a metatarsal pad, a drive circuitelectronically coupled to said electrodes, a processor electronicallycoupled to said drive circuit, and a non-transitory computer-readablemedium electronically coupled to said processor and comprisinginstructions stored thereon that, when executed on said processor,perform the steps of: receiving information regarding said measuredfirst capacitance from said drive circuit, comparing said measured firstcapacitance to a first DFU reference value, wherein said first DFUreference value is a measurement of a second capacitance of apre-selected second region of tissue on a second foot that isbisymmetric to said pre-selected first region of foot tissue withrespect to a centerline of the body, receiving information regardingsaid first DFU reference value from said drive circuit, determining adifference between said measured first capacitance and said first DFUreference value, and providing a first notification if the difference isgreater than a first predetermined threshold.
 2. (canceled) 3.(canceled)
 4. The apparatus of claim 1, wherein said first DFU referencevalue is determined from measurements of said second capacitance at saidpre-selected second region of tissue on said second foot at one or moretimes prior to the most recent measurement of said first capacitance. 5.(canceled)
 6. (canceled)
 7. The apparatus of claim 1, wherein saidpre-selected second region of tissue on said second foot is known to behealthy.
 8. The apparatus of claim 1, wherein said second capacitance ismeasured at approximately the same time as said first capacitance. 9.The apparatus of claim 1, the apparatus further comprising one or moretemperature sensors that are configured to measure a first temperatureof said pre-selected first region of tissue on said first foot and arecoupled to said processor, wherein: said instructions further comprisethe steps of: receiving information regarding said measured temperaturefrom said one or more temperature sensors, and comparing said measuredtemperature to a second DFU reference value, and providing a secondnotification if said measured first capacitance differs from said firstDFU reference value by an amount greater than said predetermined firstthreshold and said measured temperature differs from said second DFUreference value by an amount greater than a predetermined secondthreshold.
 10. The apparatus of claim 1, the apparatus furthercomprising one or more optical sensors configured to image an undersideof said first foot or said second foot of a patient while said patientis standing on said substrate. 11-30. (canceled)
 31. The apparatus ofclaim 1, the apparatus further comprising: at least two stimuluselectrodes disposed on the substrate such that a portion of a currentpassing between a pair of the stimulus electrodes will pass through aportion of said preselected first region of tissue; and an externalcontroller electrically connected to said at least two stimuluselectrodes and configured to provide a therapeutic stimulus to saidpreselected first region of tissue.
 32. The integrated apparatus ofclaim 31, wherein said external controller is further configured tocontrol said two electrodes to detect conductive contact with thepatient’s skin during a sensing phase and to apply said therapeuticstimulus to the patient during a therapeutic phase.